Naringenin induces apoptosis through downregulation of Akt and caspase-3 activation in human leukemia THP-1 cells.
Naringenin (NGEN), one of the most abundant flavonoids in citrus fruits, has been shown to inhibit in vitro growth of in human cancer cells, although the mechanism of action is poorly understood. Herein, we investigated NEGN's pro-apoptotic effect on human leukemia THP-1 cells. NGEN treatment inhibited THP-1 cells' growth a concentration-dependent manner by inducing apoptosis, as evidenced by the formation of apoptotic bodies and the accumulation of cells in the sub-G1 phase. NGEN-induced apoptosis was accompanied by increased hyperpolarization of the mitochondrial membrane potential, downregulation of Bcl-2, upregulation of Bax, activation of caspases and subsequent poly(ADP-ribose)polymerase (PARP) cleavages. z-DEVD-fmk, a caspase-3 inhibitor, significantly inhibited both the cytotoxic effect and apoptotic characteristics induced by NGEN treatment demonstrating caspase-3's important role in the observed cytotoxic effect. The induction of apoptosis was also associated with the inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt, and PI3K inhibitor LY29004 significantly increases NGEN-induced cell death. These findings provide evidence that NEGN's pro-apoptotic effect is mediated by the activation of caspases and mitochondria dysfunctions that correlate with the inactivation of the PI3K/Akt pathway in THP-1 cells. Therefore, NGEN has a strong potential as a therapeutic agent for preventing cancers such as leukemia.
Park
Joon Hee
JH
Department of Molecular Biology, Dongeui University, South Korea.
Jin
Cheng-Yun
CY
Lee
Bok Kyu
BK
Kim
Gi-Young
GY
Choi
Yung Hyun
YH
Jeong
Yong Kee
YK
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology*; D044950:Flavanones / Q000494:pharmacology*; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D051058:Oncogene Protein v-akt / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D004965:Estrogen Antagonists; D044950:Flavanones; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D007211:Indoles; C007293:DAPI; D051058:Oncogene Protein v-akt; D053148:Caspase 3; C005273:naringenin